14
Nonneoplastic Respiratory Diseases

In persons who smoke, the cells that line the bronchi and alveoli come into direct contact with high concentrations of tobacco toxicants. Not surprisingly, respiratory diseases such as chronic obstructive pulmonary disease (COPD) are major health problems in smokers (Murin and Silvestri, 2000). Tobacco-related respiratory diseases predominately affect male smokers, but the prevalence of COPD in women is rising rapidly and it appears to follow the prevalence of smoking by 20–30 years (Tanoue, 2000). Children exposed to environmental tobacco smoke (ETS) are also affected (Joad, 2000). Because low levels of tobacco toxicants from ETS come in direct contact with the lung, it is necessary to consider the health effects of both mainstream and secondary smoke.

In evaluating harm reduction strategies for tobacco-related lung diseases, three major nonneoplastic respiratory diseases linked to cigarette smoking must be considered: COPD, asthma, and respiratory infections. Numerous other respiratory diseases are strongly related to cigarette smoking as shown in Table 14–1 (Murin et al., 2000). The relative risks of mortality due to smoking-related nonneoplastic respiratory diseases are considerable, and approximately 91,000 Americans died annually of respiratory diseases attributed to smoking during 1990–1994 (Table 14–1 and 14–2) (Novotny and Giovino, 1998). Cigarette smoking is estimated to contribute to 80–90% of cases of COPD, and the amount and duration of cigarette smoking directly influence the progression of COPD. Asthma and respiratory infections, on the other hand, are not caused by tobacco smoke but are worsened by exposure to cigarette smoke. Of special im-



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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction 14 Nonneoplastic Respiratory Diseases In persons who smoke, the cells that line the bronchi and alveoli come into direct contact with high concentrations of tobacco toxicants. Not surprisingly, respiratory diseases such as chronic obstructive pulmonary disease (COPD) are major health problems in smokers (Murin and Silvestri, 2000). Tobacco-related respiratory diseases predominately affect male smokers, but the prevalence of COPD in women is rising rapidly and it appears to follow the prevalence of smoking by 20–30 years (Tanoue, 2000). Children exposed to environmental tobacco smoke (ETS) are also affected (Joad, 2000). Because low levels of tobacco toxicants from ETS come in direct contact with the lung, it is necessary to consider the health effects of both mainstream and secondary smoke. In evaluating harm reduction strategies for tobacco-related lung diseases, three major nonneoplastic respiratory diseases linked to cigarette smoking must be considered: COPD, asthma, and respiratory infections. Numerous other respiratory diseases are strongly related to cigarette smoking as shown in Table 14–1 (Murin et al., 2000). The relative risks of mortality due to smoking-related nonneoplastic respiratory diseases are considerable, and approximately 91,000 Americans died annually of respiratory diseases attributed to smoking during 1990–1994 (Table 14–1 and 14–2) (Novotny and Giovino, 1998). Cigarette smoking is estimated to contribute to 80–90% of cases of COPD, and the amount and duration of cigarette smoking directly influence the progression of COPD. Asthma and respiratory infections, on the other hand, are not caused by tobacco smoke but are worsened by exposure to cigarette smoke. Of special im-

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction TABLE 14–1 Smoking-Affected Pulmonary Diseases Disease Incidence or Severity Definitely Increased by Smoking Common cold Influenza Bacterial pneumonia Tuberculosis infection Invasive pneumococcal infection Pulmonary hemmorrhage Pulmonary metastatic disease Spontaneous pneumothorax Eosinophillic granuloma Respiratory bronchiolitis-associated interstitial lung disease Idiopathic pulmonary fibrosis Asbestosis Rheumatoid arthritis-associated interstitial lung disease Disease Incidence or Severity Possibly Decreased by Smoking Sarcoidosis Hypersensitivity pneumonitis NOTE: Modified with permission from Murin et al., 2000. Copyright (2000) by W.B. Saunders Company. portance in considering harm reduction strategies is the contribution of ETS to asthma and respiratory infections in children. Abatement strategies for susceptible children exposed to environmental tobacco smoke may differ from those used to reduce harm in tobacco smokers. An extensive knowledge base exists describing the contribution of tobacco smoke exposure to nonneoplastic respiratory disease, and key points are described briefly here. The major goal of this chapter is to summarize studies designed to test whether reducing exposure to tobacco toxicants improves health outcomes for respiratory diseases. As will be described below, there are considerable gaps in information about reducing harm and uncertainties about the quality of the existing knowledge base in this regard. Consequently, a research agenda is proposed to guide future studies aimed at reducing the harm from smoking in COPD. BIOMARKERS OF RESPIRATORY DISEASES There are currently no specific biomarkers of respiratory disease due to smoking tobacco products (see Chapter 11). The rare genetic deficiency of α1-antitrypsin is a risk factor for disease, not a biomarker (see below). No unique molecular or genetic defect specific for tobacco-related respi-

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction TABLE 14–2 Relative Risk (RR) for Smoking-Attributable Mortality and Average Annual Smoking-Attributable Respiratory Disease Mortality (SAM) Among Current and Former Smokers, by Sex and Disease, United States, 1990–1994   Men Women   Respiratory Disease Current Smokers RR Former Smokers RR SAM Current Smokers RR Former Smokers RR SAM Total SAM Pneumonia, influenza 2.0 1.6 11,267 2.2 1.4 8,060 19,327 Bronchitis, Emphysema 9.7 8.8 9,642 10.5 7.0 6,475 16,117 Chronic airway obstruction 9.7 8.8 32,132 10.5 7.0 21,893 54,025 Other respiratory diseases 2.0 1.6 776 2.2 1.4 721 1,497 Total   53,817   37,149 90,966   SOURCE: Reprinted with modifications and permission from Novotny and Giovino, 1998. Copyright (1998) by the American Public Health Association. ratory disease has been identified. The processes involved, such as inflammation and increased levels of oxidants, are not unique to tobacco-related respiratory diseases. Identifying unique biomarkers is further confounded by the heterogeneous nature of these diseases, the complex mixture that makes up tobacco smoke, and the range of individual susceptibilities to the harmful effects of tobacco smoke among users (see Chapter 11). In COPD, for example, the majority of smokers develop abnormal lung function (Camilli et al., 1987), but only 15–20% will develop symptomatic COPD (Fletcher and Peto, 1977). There appears to be no specific clinical or physiological feature to predict which smokers exhibit a rapid decline in lung function (Habib et al., 1987). The most widely used markers of tobacco-related respiratory diseases in population studies are symptom questionnaires and pulmonary function testing. These have well-known limitations of specificity and sensitivity, particularly for detecting the early effects of tobacco smoke on lungs (U.S. DHHS, 1989). Subtle effects of tobacco smoke exposure on the lung can be detected by sampling fluid in

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction the lower respiratory tract via a bronchoscope inserted into the airways, but the significance of these changes to clinically important pulmonary disease has not been established. Newer approaches such as sampling the subjects’ urine (Pratico et al., 1998) or exhaled gas (Ichinose et al., 2000; Paolo et al., 2000) for metabolic products due to tissue injury have the advantage of noninvasive sampling but must be validated. Clearly, the greatest obstacle for developing a specific biomarker is the lack of fundamental information on mechanisms by which exposure to tobacco smoke causes specific respiratory diseases. Insight into understanding the molecular basis of diseases may come from unraveling the complex interactions between genetic makeup and the environment that could evolve from the Human Genome Project or similar molecular studies. CHRONIC OBSTRUCTIVE PULMONARY DISEASE Definition and Epidemiology Chronic obstructive pulmonary disease is an all-inclusive term that encompasses chronic bronchitis (the presence of chronic productive cough) and emphysema (permanent enlargement of the distal airspaces) (Aubry et al., 2000). Usually, chronic bronchitis and emphysema occur in combination. The major clinical features of COPD are chronic cough, expectoration of sputum, breathlessness during exertion, and airflow obstruction on forced expiration that tends to worsen over time (Barnes, 2000; Piquette et al., 2000). The natural history of COPD and its health care implications have been extensively reviewed (Hensley and Saunders, 1989). The course of COPD is characterized by loss of ventilatory function from the peak attained in early adulthood (Figure 14–1). Clinical symptoms of COPD develop after substantial loss of ventilatory function, typically in the fourth and fifth decades of life. In longitudinal studies, the average loss of function in nonsmokers begins at about age 30 as assessed by the relationship of change in forced expiratory volume at 1 second (FEV1) with age. In nonsmokers, this amounts to about 20 ml per year. The rate of decline in FEV1 is somewhat greater (40 ml per year) in smokers of 30 cigarettes per day compared to nonsmokers (Camilli et al., 1987; Fletcher and Peto, 1977). A subset of smokers, who will develop COPD, lose function more rapidly (60 ml per year; Habib et al., 1987). However, there is variation in these rates and the rate of decline increases with age (Camilli et al., 1987; Fletcher and Peto, 1977). Smokers who cease smoking do not regain lost function, but the rate of decline of FEV1 slows to that of nonsmokers (Burrows, 1990). Loss of lung function appears to be a risk factor for mortality even among “never smokers” (Ashley et al., 1975; Beaty et al.,

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction FIGURE 14–1 FEV1 NOTE: Scheme showing loss of forced expiratory volume at 1 second (FEV1) with age. Nonsmokers lose lung function with age, about 30 ml per year. Smokers of 30 cigarettes/day have a greater rate of loss (dashed line). A small proportion of smokers (10–15%) have a steeper rate of decline, about 60 ml per year (dot and dashed line). This susceptible group of smokers reaches an FEV1 of 0.8 liter (the level at which shortness of breath occurs on activities of daily living) at approximately 60–70 years of age. If a susceptible smoker stops smoking at age 50, the rate of decline follows that of the nonsmoker (dotted line), showing that smoking cessation may prolong onset of symptoms. SOURCE: Reprinted with permission from Piquette, et al., 2000. Copyright (2000) by W.B. Saunders Company.

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction 1985). A loss of lung function may reflect other diseases such as heart disease that decrease life expectancy (Beaty et al., 1985). The annual number of deaths attributable to chronic airway obstruction, bronchitis, and emphysema in the United States during 1990–1994 was 70,000 (Table 14–2). The relative risk of death from COPD in smokers who have symptoms is reduced by cessation, but remains almost as high as that of current smokers. Many of those who eventually die of COPD suffer from prolonged disability due to dyspnea, cough, and sputum production. Pathogenesis The role of inflammation and exposure to toxins in cigarette smoke is central to the pathogenesis of COPD (Aubry et al., 2000). There is considerable evidence to support the theory that pulmonary emphysema is caused by excessive exposure to elastolytic enzymes in relation to inhibitors of these enzymes, the “protease-antiprotease” theory (Barnes, 2000; Piquette et al., 2000). Cigarette smoke promotes injury to the lungs by increasing the proteolytic burden and compromising the antiproteolytic defenses leading to a breakdown in lung structure. The major antiproteolytic protein in the lower respiratory tract is α1-antitrypsin (α1-AT), although other proteinase inhibitors play a lesser role (Senior and Shapiro, 1998). In chronic bronchitis, an inflammatory airway response caused by chronic exposure to airborne toxins (cigarette smoke, dust, air pollutants) is the central pathogenic mechanism (Barnes, 2000; Piquette et al., 2000). Inflammation leads to edema, cellular infiltration, fibrosis, smooth-muscle hypertrophy, and secretions that narrow the bronchioles. Animal models of emphysema and chronic bronchitis have been used to study the pathophysiology of COPD (Drazen et al., 1999; Shapiro, 2000), including the contribution of tobacco smoke (Witschi et al., 1997) (see Chapter 10). Several etiologic factors in COPD have been investigated with regard to cigarette smoking (Sethi and Rochester, 2000). One factor is airway hyperreactivity, measured by the provocation of airway constriction following inhalation of a bronchoconstricting drug or physical condition. Several longitudinal studies have shown that airway hyperreactivity is related to accelerated decline in lung function in cigarette smokers (Frew et al., 1992; O’Conner et al., 1995; Postma et al., 1986; Rijcken et al., 1995; Tashkin et al., 1996; Tracey et al., 1995). Hyperresponsiveness in the presence of blood eosinophilia increases the risk of developing respiratory symptoms (Jansen et al., 1999). If airway hyperreactivity plays a role in the progression of COPD, it is possible that regular use of bronchodilators may slow the rate of decline. However, this conclusion was not supported by the Lung Health Study (Anthonisen et al., 1994; see below).

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction Special tests of “small-airway” function were developed in the late 1960s and early 1970s to detect early changes in small airways (less than 2-mm diameter) that were are not detected on standard tests of pulmonary function (U.S. DHHS, 1984). When applied to prospective studies of populations, tests of small-airway function were not predictive for susceptible subjects who would progress to clinically significant airflow obstruction (U.S. DHHS, 1984). In subjects who exhibit accelerated deterioration of lung function (greater than 60 ml per year), this type of physiological testing was not predictive of the rate of development of clinically significant airway obstruction, probably because of the heterogeneous nature of COPD (Habib et al., 1987). Mucous hypersecretion and infections have been postulated to play roles in the accelerated decline of pulmonary function in COPD. In adults, prospective studies have failed to show an association between acute chest infections and the rate of decline of FEV1 (Bates, 1973). Chronic mucous hypersecretion in earlier studies (Fletcher and Peto, 1977; Higgins et al., 1982; Kauffmann et al., 1989; Peto et al., 1983) was not shown to be related to a decline in FEV1 in COPD. More recent studies in larger samples of the general population have shown associations between chronic mucous hypersecretion and a decline in FEV1 (Lange at al., 1990; Sherman et al., 1992; Vestbo et al., 1996). In children, however, population studies suggest that childhood respiratory infection is a risk factor for the development of COPD in adults (Gold et al., 1989; Samet et al., 1983). The role of infections is unclear, but it is believed that bacterial colonization/ infection stimulates inflammatory responses that cause local damage and progression of disease. In addition, infections impair host defenses and tissue repair, leading to further infection and perpetuating tissue injury (Murphy and Sethi, 1992). Considerable evidence from human and laboratory studies suggest that oxidant-antioxidant imbalance in favor of oxidants occurs in COPD (Figure 14–2). The evidence is based on a large number of studies showing an increased oxidant burden and markers of oxidative stress in the airspaces, breath, blood, and urine of smokers and patients with COPD (Koyama and Geddes, 1998; Macnee and Rahman, 1999). Oxidants in patients with COPD are derived from oxygen free radicals in both the gas and tar phases of cigarette smoke (Pryor and Stone, 1993; Zang et al., 1995). Inflammation itself induces oxidant stress in the lungs of smokers as suggested by studies showing greater production of oxygen free radicals by leukocytes in smokers compared to nonsmokers (Morrison et al., 1999) and increased iron content, which promotes formation of free radicals in alveolar macrophages of smokers (Mateos et al., 1998). Pathological examination of the alveolar regions of smokers’ lungs has shown increases in the number and percentage of leukocytes compared to non

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction FIGURE 14–2 Pathogenesis of emphysema. NOTE: Scheme of smoking-induced pulmonary emphysema. Smoking recruits inflammatory cells to the lower respiratory system via stimulation of alveolar macrophages. Inflammatory cells release enzymes (peroxidase, myeloperoxidase) and oxygen free radicals that degrade the extracellular matrix of the respiratory tissues and interfere with normal repair mechanisms. Tobacco smoke also contains oxygen free radicals that, together with products released from inflammatory cells, inactivate protease inhibitors such as α1-AT. SOURCE: Reprinted with permission from Senior and Shapiro, 1998. Copyright (1998) by McGraw-Hill Companies. smokers (Hunninghake and Crystal, 1983). Recent studies have utilized analysis of exhaled gas in patients with COPD for gaseous products (i.e., reactive nitrogen species, ethane)(Ichinose et al., 2000; Paolo et al., 2000) and urinary products (isoprostane F2-α-III) (Pratico et al., 1998) formed from oxidative stress. It is possible that measurement of products of oxidative stress in exhaled gas may be used as surrogate markers of inflammation in COPD. A possible mechanism whereby oxidants damage the lung is by inactivating the antielastase α1-AT, thereby decreasing the ca-

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction pacity of α1-antitrypsin to inhibit proteases (Carp et al., 1982; Johnson and Travis, 1979). This mechanism has been expanded to include proteinases other than neutrophil elastase and antiproteinases other than α1-AT (Senior and Shapiro, 1998). Dietary deficiency of antioxidants has been proposed as a factor accounting for airflow limitation in elderly people (Dow et al., 1996), but dietary supplements of antioxidants have not been shown to modify clinical symptoms of COPD (Macnee and Rahman, 1999; Rautalahti et al., 1997; Traber et al., 2000). Mainstream Smoke Exposure The predominant risk factor for COPD is cigarette smoking, and it is estimated to account for 80–90% of the risk of developing COPD (U.S. DHHS, 1984). Cigarette smoking is associated with a lower FEV1 in cross-sectional studies (Burrows et al., 1977a; Dockery et al., 1988; Knudson et al., 1976) and with an accelerated decline in FEV1 in longitudinal studies (reviewed in Sherman, 1991). The lower FEV1 in cross-sectional studies and accelerated rate of decline in FEV1 exhibit a dose-response relationship. Both the duration of smoking and the amount smoked are significant predictors of lung function impairment (U.S. DHHS, 1989). Individuals who smoke have age-adjusted death rates for COPD that are tenfold higher than those of never smokers (U.S. DHHS, 1989). Mortality and morbidity rates for COPD are higher in pipe and cigar smokers than nonsmokers, although the rates are lower than in cigarette smokers. Factors predictive of COPD mortality include age at starting, current smoking status, and total pack-years. For reasons that are not known, only about 15% of smokers develop clinically significant COPD (Fletcher and Peto, 1977). Data suggest that 10–15% of COPD cases are attributable to causes other than smoking, including occupational exposures to coal dust (Marine et al., 1988), grain dust (Zejda et al., 1993), air pollution (Bates, 1973; Buist and Vollmer, 1994; Rokaw et al., 1980), childhood respiratory infections (Burrows et al., 1977b; Shaheen et al., 1995), and airway hyperresponsiveness (Buist and Vollmer, 1994). Genetic factors that are independent of personal smoking history or environmental exposures also contribute to COPD (Khoury et al., 1985). These include a1-antitrypsin deficiency, which accounts for less than 1% of cases of COPD (Snider, 1989). Additional genetic factors other than α1-AT deficiency that appear to play a role in susceptibility to COPD have not been identified (Khoury et al., 1985). Prospective population studies have shown an additive effect of air pollution on the decline in lung function in smokers (Tashkin et al., 1994;

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction van der Lende et al., 1981). In a cohort study examining the additive effects of smoking and pollution on lung function decline, the mean adjusted decrement in FEV1 attributable to smoking more than 24 cigarettes a day was 17.4 ml per year. An adjusted mean annual decrease of 8.9 ml per year was attributed to living in a moderately polluted environment compared to living in a clean environment (van der Lende et al., 1981). The conclusion of this study was that the decline in lung function attributable to smoking was twice as great when living in a polluted environment. In a prospective study of persons living in three communities with air pollution, a significant interaction between smoking more than 12 cigarettes a day and area of residence was found for mean decline of adjusted FEV1 in males (Tashkin et al., 1994). These findings suggest an independent adverse effect of air pollution on decline of lung function in smokers. Environmental Tobacco Smoke Exposure Adults Coultas (1998) has reviewed published reports of an association between ETS exposure and COPD. He classified three types of studies: two categories based on “indirect” measures of COPD (self-reports of symptoms of COPD; effects on lung function measurements) and a third category that used “direct” measures of COPD (mortality and hospitalizations). The studies focused on environmental tobacco smoke as a risk factor for developing COPD, not as factor that contributed to worsening of symptoms or lung function. In regard to self-reported outcomes, Coultas (1998) summarized the results of three studies (Dayal et al., 1994; Leuenberger et al., 1994; Robbins et al., 1993) published since the Environmental Protection Agency (EPA) report (EPA, 1993) that concluded environmental tobacco smoke “may increase the frequency of respiratory symptoms in adults.” Results of one population-based survey of self-reported COPD suggest that 3–5% of nonsmokers may be affected (Whittemore et al., 1995). The three published reports combined asthma and COPD. These studies all report similar findings that passive smoking is associated with chronic respiratory symptoms found in adults with COPD. The second type of study examined declines in lung function and passive smoking in the development of COPD. Epidemiological studies have investigated the association between environmental tobacco smoke, respiratory diseases, and reduction in pulmonary function tests (Sherman, 1991; Tredaniel et al., 1994). It is controversial whether ETS exposure is

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction associated with COPD. Some studies have reported greater reduction in pulmonary function in nonsmokers married to smokers and exposed to environmental tobacco smoke in the workplace (Berglund et al., 1999; Hole et al., 1989; Leuenberger et al., 1994; Svendsen et al., 1987; White and Froeb, 1980). However, most of the studies used sensitive indicators of lung function, and the physiological significance of small changes in lung function to COPD is not established. In addition, the effect of bias and confounding factors were not taken into account. No relation between passive smoking and reduced lung function in adults was found in two large cross-sectional studies (Comstock et al., 1981; Schottenfeld, 1984) and one longitudinal study (Jones et al., 1983). Thus, whether environmental tobacco smoke causes COPD in adults remains uncertain. Current evidence suggests that the development of COPD in adults results from impaired lung development and growth in childhood, premature onset of declines in lung function, and/or accelerated decline in lung function (Fletcher et al., 1976; Kerstjens et al., 1997; Samet and Lange, 1996). Although passive smoking is a biologically plausible risk factor, the impact of passive smoking during adulthood on the development of COPD remains controversial. In a review of this topic, Tredaniel and associates (1994) summarized the results of 18 relevant publications. Eight reports found no effect of ETS exposure on lung function, and ten demonstrated small decrements. The authors pointed out the methodological limitations of these studies and raised questions about the relevance of small declines in lung function to the development of COPD. Coultas (1998) reviewed the results of three additional studies published since the Tredaniel et al. (1994) review and concluded that the results were inconsistent (two showing no effect and one showing an effect). In the study showing an effect, a large sample of never-smoking adults in Switzerland (Leuenberger et al., 1994), the association between increased symptoms of chronic bronchitis and environmental tobacco smoke was dose-related. The adjusted odds ratio of chronic bronchitis symptoms increased by years of exposure to environmental tobacco smoke, number of smokers to whom the subject was exposed, and workplace exposures (Leuenberger et al., 1994). An additional report published after Coultas’ review concluded that environmental tobacco smoke in adults is associated with small defects in lung function (Carey et al., 1999). Children Exposure to passive smoking in childhood has been associated with reduced rate of growth of the lung as determined by change of ventilatory function with age in children exposed to environmental smoke compared to unexposed children (Berkey et al., 1986; Tager et al., 1979, 1983, 1987)

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction The availability of dose-effect data and validated biomarkers may improve the quality of, and provide greater confidence in, the results of contemplated intervention studies. However, the time frame for generating dose-effect data and testing biomarkers is uncertain, and it is unclear whether inclusion of dose-effect considerations and biomarkers will improve the quality of clinical trials of harm reduction in respiratory diseases. An alternative is to proceed with interventional trials based on current knowledge if there are uncertainties about the added value of dose-effect data or untested biomarkers to study design. As an example, an intervention study of the effect of smoking reduction on COPD could be considered that is similar in design to the Lung Health Study, a large prospective trial of the effects of smoking cessation on rate of decline of FEV1 in middle-aged smokers with mild COPD (Anthonisen et al., 1994). Another approach is to conduct a trial using a low-tar/moderate-nicotine product from a noncommercial source to avoid product endorsement issues. (A more detailed research agenda can be found in the next section.) Design of population studies for harm reduction of major respiratory diseases is challenging because of uncertainties about effectiveness and long-term compliance with harm reduction interventions. Reducing the burden of tobacco-related respiratory diseases through harm reduction strategies should be a major priority of the nation’s public health. RESEARCH AGENDA This section outlines a suggested research agenda for studying harm reduction due to cigarette smoking in respiratory diseases (i.e., COPD, asthma, respiratory infections). Several specific suggestions for research design arise from this review. An interventional study of the effect of smoking reduction on COPD could be considered that is similar in design to the Lung Health Study, a large prospective trial of the effects of smoking cessation on rate of decline of FEV1 in middle-aged smokers with mild COPD (Anthonisen et al., 1994). In a proposed smoking reduction trial, it might be possible to include an intervention group of smokers who are able to reduce their smoking spontaneously and maintain significant reductions for a long period using behavior intervention and/or nicotine replacement products. The goal would be to decrease the number of cigarettes per day to eight to ten, a point below which it is very difficult to reduce the number of cigarettes smoked (Hughes, 2000). The primary end point could be the change in FEV1 over five years, and secondary end points could be exhaled carbon monoxide concentration, serum cotinine level, survival, and comorbid smoking-related disorders. If successful, this study should be

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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction able to determine whether reduced smoking as measured by change in FEV1 mitigates harm to the lungs. Potential weaknesses are the self-selection of subjects, the large number of subjects required, ethical issues regarding the nonintervention group, and a probable large dropout rate in the intervention group. Another approach is to conduct a trial using a low-tar/moderate-nicotine product from a noncommercial source to avoid product endorsement issues. This study might be conducted in two phases. Phase I would be a controlled-exposure study in human smokers to compare the effects of the low-tar/moderate-nicotine product versus a reference cigarette on inflammatory changes in the lower respiratory tract, similar to the observations of Rennard et al. (Rennard, 2000). The objective of Phase I would be to determine if inflammation is reduced by exposure to the low-tar/ moderate-nicotine product. If so, a Phase II intervention trial would compare the low-tar/moderate nicotine product to reference cigarettes in cohorts of current smokers. The objectives and design of the Phase II trial would be similar to that described above for intervention using behavioral modification or NRT. Potential advantages of this trial are that the low-tar/moderate-nicotine product, if it reduces harm, could be used as a reference product for future regulation of marketed products. Uncertainties related to such a study include inference from results of short-term controlled exposures to longer-term studies, controlling use of the intervention product, and the large effort that would be needed to complete the study. REFERENCES Abramson M, Kutin J, et al. 1995. Morbidity, medication and trigger factors in a community sample of adults with asthma. Med J Aust 162:78–81. Alcaide J, Altet M, et al. 1996. Cigarette smoking as a risk factor for tuberculosis in young adults: a case-control study. Tubercle and Lung Disease 77:112–116. Altet M, Alcaide J, et al. 1996. Passive smoking and risk of pulmonary tuberculosis in children immediately following infection. A case-control study. Tubercle and Lung Disease 77:537–544. Althuis MD, Sexton M, Prybylski D. 1999. Cigarette smoking and asthma symptom severity among adult asthmatics. J Asthma 36(3):257–264. Anderson R, Sy F, et al. 1997. Cigarette smoking and tuberculin skin test conversion among incarcerated adults. Amer J Prev Med 13:175–181. Anthonisen NR, Connett JE, Kiley JP, et al. 1994. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 272(19):1497–1505. Aronson MD, Weiss ST, Ben RL, Komaroff AL. 1982. Association between cigarette smoking and acute respiratory tract illness in young adults. JAMA 248(2):181–183. Ashley F, Kannel WB, Sorlie PD, Masson R. 1975. Pulmonary function: relation to aging, cigarette habit, and mortality. The Framingham Study. Ann Intern Med 82:739–745.

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